1. Field of the Invention
This invention relates to methods and compositions which can be employed in the prophylaxis, treatment and management of liver disorders, especially those characterized by inflammation. Also disclosed are methods and reagents useful in the prognosis and diagnosis of inflammatory liver disorders.
2. Description of Related Disclosures
The recruitment and recirculation of leukocytes from blood, through tissue, into lymph and back to the blood are key events in the inflammatory process associated with tissue injury, infection or antigen deposition (Springer, T., (1994) Cell, 76:301–314; Berlin et al., (1995) Cell, 80:413–422; Schweighoffer et al., (1993) J. Immunol., 151:717–729). These events are regulated at a molecular level by interactions between various specialized molecules on the surface of circulating leukocytes and vascular endothelial cells (Springer, T., (1994) supra). Recent models indicate that the recruitment or homing of peripheral blood leukocytes, including lymphocyte subsets, to various tissue sites proceeds by a multistep process comprising i) a primary transient contact event, ii) a rapid activating event that involves G protein-linked signaling receptors and iii) activation triggered firm adhesion (Springer et al., (1994) supra). Chemotaxis and extravasation of leukocytes into tissue follows these three primary events.
The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is involved in the selective homing of lymphocytes to normal mucosal tissues (Berlin et al., (1993) Cell, 74:185–195; Briskin et al., (1997) Am. J. Pathol. 151:97–110). It is expressed on a restricted set of vessels including high endothelial venules (HEV's) of the mucosal associated lymphoid tissues and directs lymphocyte traffic to Peyer's patches and the intestinal lamina propria (Berlin et al., (1993) supra). In humans, MAdCAM-1 expression has been associated with tissues of the gastrointestinal tract (colon and small intestine) and associated lymphoid tissues (mesenteric lymph nodes)(Briskin et al., (1997) supra). It has been detected in pancreas, gall bladder and splenic venules and marginal sinus of the splenic white pulp (Kraal et al., (1995) Am. J. Path. 147:763–771). In inflammatory settings increased MAdCAM-1 expression has been observed in HEV like vessels in the pancreas of non-obese diabetic mice (Hanninen A., et al., (1993) J. Clin. Invest 92:2509), on intestinal lamina propria venules from mice with experimentally induced inflammatory bowel disease (Viney J. et al., (1996) J. Immunol. 157:2488–2497; Picarella D., et al., (1997) J. Immunol., 158:2099–2016) and in humans at inflammatory foci associated with ulcerative colitis and Crohn's disease (Briskin et al., (1997) supra). It has not been detected in the majority of normal or inflamed extra-intestinal tissues (Briskin et al., (1997) supra).
The lymphocyte integrin α4β7 has been shown to mediate lymphocyte (memory T cells) adhesion to MAdCAM-1 (Tidwell et al., J. Immunol. 159:1497–1505; Walsh et al., (1996) Immunol. 89:112–119; Berlin et al., (1993) Cell, 74:185–195). The MAdCAM-1/α4β7 interaction has been shown to mediate selectin-independent interaction and rolling of lymphocytes under physiological flow (Berlin et al., (1995) Cell, 80:413–422).
Antibodies to MAdCAM-1 and both the α4 and β7 subunit of the α4β7 integrin block lymphocyte binding to cells expressing MAdCAM-1 (Berlin et al., (1993) Cell, 74:185–195). It has been shown that MAdCAM-1/α4β7 blockade reduces lymphocyte trafficking and decreases the severity of the inflammatory infiltrate and the degree of tissue injury in experimental models of chronic inflammatory bowel disease (Picarella et al., (1997) J. Immunol. 158(5):2099–2106; Hesterberg et al., (1996) Gastroenterology 111:1373–1380). Several potent inhibitors of the MAdCAM-1/α4β7 interaction have been proposed for preventing MAdCAM-1 associated leukocyte recruitment to the gastrointestinal tract (International Publication No. WO 96/24673, International Publication No. WO 97/25351).